scholarly journals Mild Progressive Osseous Heteroplasia Overlap Syndrome With PTH and TSH Resistance Appearing During Adolescence and Not Early Childhood

2021 ◽  
Author(s):  
Kayo Ozaki ◽  
Akari Mituboshi ◽  
Masashi Nagai ◽  
Atushi Nishiyama ◽  
Gen Nishimura ◽  
...  
Keyword(s):  
Early Childhood ◽  
Dna Analysis ◽  
Genetic Disorder ◽  
Overlap Syndrome ◽  
Heterozygous Mutation ◽  
Loading Test ◽  
Ectopic Ossification ◽  
Old Japanese ◽  
Inactivating Mutations ◽  
Progressive Osseous Heteroplasia

Abstract Purpose: Progressive osseous heteroplasia (POH), a genetic disorder, is associated with Albright’s hereditary osteodystrophy (AHO), pseudohypoparathyroidism, and primary osteoma cutis and has common features of superficial ossification and GNAS-inactivating mutations. Disorders due to GNAS­-inactivating mutations are classified as “inactivating parathyroid hormone (PTH)/PTHrP signaling disorder type 2.” This study reports a case of mild POH overlap syndrome to improve understanding of genotype–phenotype correlations.Methods: A 13-year-and-6-month-old Japanese boy was referred to our hospital with a chief complaint of the lower limb length difference. He underwent clinical, biochemical, radiological, and genetic studies.Results: He showed sporadic GNAS mutation, deep ectopic ossification, small for gestational age (SGA), congenital tooth defect, and lack of AHO features; he met the diagnostic criteria for POH, and mild PTH and TSH resistance was detected. He had constant hyperphosphatasemia and hypocalciuria. At the age of 10 years, he occasionally experienced high iPTH levels. The pituitary stimulation test showed a normal response of all hormones at 3 years of age, but TSH response was decreased (previously 0.770, peak value 4.144 μIU/mL) in the TRH loading test at age 13 years and 6 months. DNA analysis showed a heterozygous p.D189MfsTer14 mutation of GNAS. The parents did not carry this mutation.Conclusion: We report a rare case of POH overlap syndrome with PTH/TSH resistance that appeared in adolescence rather than early childhood. Cases diagnosed with POH in early childhood also require reassessment during adolescence. Further studies of the GNAS heterozygous mutation p.D189MfsTer14 may reveal factors involved in POH overlap syndrome.

scholarly journals Mild progressive osseous heteroplasia overlap syndrome with PTH and TSH resistance appearing during adolescence and not early childhood

Endocrine ◽  
2021 ◽  
Author(s):  
Kayo Ozaki ◽  
Akari Mituboshi ◽  
Masashi Nagai ◽  
Atushi Nishiyama ◽  
Gen Nishimura ◽  
...  
Keyword(s):  
Early Childhood ◽  
Overlap Syndrome ◽  
Progressive Osseous Heteroplasia

scholarly journals Drug repositioning for a rare genetic disorder progressive osseous heteroplasia (POH)

Genetika ◽  
2019 ◽  
Vol 51 (1) ◽  
pp. 347-355
Author(s):  
Jelena Gvozdenovic-Jeremic ◽  
Ljiljana Mojovic
Keyword(s):  
Drug Repositioning ◽  
Genetic Disorder ◽  
Potential Candidate ◽  
Molecular Signaling ◽  
Mice Model ◽  
Connective Tissues ◽  
Ectopic Ossification ◽  
Gene Encoding ◽  
Ectopic Bone ◽  
Progressive Osseous Heteroplasia

Progressive osseous heteroplasia (POH) is an ultrarare genetic disease of progressive ectopic ossification caused by heterozygous inactivating mutations of GNAS, the gene encoding the alpha subunit of the G-stimulatory protein of adenylyl cyclase (Gs?). Extensive ossification of the deep connective tissues can result in ankylosis of affected joints and growth retardation of involved limbs. Inhibition of main molecular signaling, Hedgehog (Hh) pathway, by pharmacological methods may reduce the severity of ectopic bone formation in POH patients. Hh inhibitors currently used or known for other conditions may be potential candidate drugs for treating this debilitating disease. In this study, three potential Hedgehog pathway inhibitors such as arsenic trioxide, statin, and vitamin D and their combinations were tested on subcutaneous mesenchymal progenitor (SMP) cells of G?s f/f mice model for possible therapeutic application for POH. The combination of these three drugs at their significantly reduced concentrations retained anti-osteogenic activity in SMP cells with aberrant Hedgehog activity. In that light, we propose here a potential new approach of the drug combination in order to reduce potential toxicity, the side effect and increase success rate for Hh inhibitors drug repositioning.

scholarly journals Protein C Gene Mutation in an Older Adult Patient with Clostridium perfringens Septicemia-Related Visceral Vein Thrombosis

TH Open ◽  
2021 ◽  
Vol 05 (02) ◽  
pp. e171-e173
Author(s):  
Kiyoko Kanosue ◽  
Satomi Nagaya ◽  
Eriko Morishita ◽  
Masayoshi Yamanishi ◽  
Shinsaku Imashuku
Keyword(s):  
Gene Mutation ◽  
Clostridium Perfringens ◽  
Protein C ◽  
Later Life ◽  
Heterozygous Mutation ◽  
Protein C Deficiency ◽  
Vein Thrombosis ◽  
Thrombosis Risk ◽  
Japanese Male ◽  
Old Japanese

AbstractA 78-year-old Japanese male with Clostridium perfringens septicemia and cholecystitis was found to have thrombosis in the left branch of intrahepatic portal vein as well as superior mesenteric vein. Visceral vein thrombosis (VVT) in this case was associated with protein C deficiency, due to a heterozygous mutation, p. Arg185Met. Our experience emphasizes that VVT, or other thromboembolic events, may occur in later life, triggered by environmental thrombosis risk factors, together with underlying hereditary protein C gene mutation.

scholarly journals Role of Signal Transduction Pathways and Transcription Factors in Cartilage and Joint Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1340 ◽  
Author(s):  
Riko Nishimura ◽  
Kenji Hata ◽  
Yoshifumi Takahata ◽  
Tomohiko Murakami ◽  
Eriko Nakamura ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Transcription Factors ◽  
Signaling Pathways ◽  
Genetic Disorder ◽  
Interleukin 1 ◽  
Genetic Diseases ◽  
Mtor Inhibitors ◽  
Joint Diseases ◽  
Ectopic Ossification ◽  
Parathyroid Hormone Related Protein

Osteoarthritis and rheumatoid arthritis are common cartilage and joint diseases that globally affect more than 200 million and 20 million people, respectively. Several transcription factors have been implicated in the onset and progression of osteoarthritis, including Runx2, C/EBPβ, HIF2α, Sox4, and Sox11. Interleukin-1 β (IL-1β) leads to osteoarthritis through NF-ĸB, IκBζ, and the Zn2+-ZIP8-MTF1 axis. IL-1, IL-6, and tumor necrosis factor α (TNFα) play a major pathological role in rheumatoid arthritis through NF-ĸB and JAK/STAT pathways. Indeed, inhibitory reagents for IL-1, IL-6, and TNFα provide clinical benefits for rheumatoid arthritis patients. Several growth factors, such as bone morphogenetic protein (BMP), fibroblast growth factor (FGF), parathyroid hormone-related protein (PTHrP), and Indian hedgehog, play roles in regulating chondrocyte proliferation and differentiation. Disruption and excess of these signaling pathways cause genetic disorders in cartilage and skeletal tissues. Fibrodysplasia ossificans progressive, an autosomal genetic disorder characterized by ectopic ossification, is induced by mutant ACVR1. Mechanistic target of rapamycin kinase (mTOR) inhibitors can prevent ectopic ossification induced by ACVR1 mutations. C-type natriuretic peptide is currently the most promising therapy for achondroplasia and related autosomal genetic diseases that manifest severe dwarfism. In these ways, investigation of cartilage and chondrocyte diseases at molecular and cellular levels has enlightened the development of effective therapies. Thus, identification of signaling pathways and transcription factors implicated in these diseases is important.

Association of Environmental Tobacco Smoke with the Risk of Severe Early Childhood Caries among 3-Year-Old Japanese Children

2018 ◽  
Vol 53 (3) ◽  
pp. 268-274 ◽  
Author(s):  
Yoshimi Nakayama ◽  
Hirofumi Ohnishi ◽  
Mitsuru Mori
Keyword(s):  
Early Childhood ◽  
Environmental Tobacco Smoke ◽  
Tobacco Smoke ◽  
Early Childhood Caries ◽  
Missing Values ◽  
Well Being ◽  
Japanese Children ◽  
Old Japanese ◽  
Severe Early Childhood Caries ◽  
Childhood Caries

Severe early childhood caries (S-ECC) has serious consequences for primary dentition, affecting the overall health, well-being, and quality of life of the child. The aim of this study was to investigate the association of risk factors, including environmental tobacco smoke (ETS), with S-ECC in 3-year-old Japanese children by a cross-sectional study. Study subjects were 2,825 children aged 3 years old. Of these individuals, after excluding the study subjects with missing values, a total of 2,277 children were included in the present analysis. The self-administered questionnaire included such items as sex, whether a smoker resides in the home, the number of smokers in the home, snack time, drinking or eating sweets after dinner, frequency of parents brushing their child’s teeth, the use of fluoride toothpaste, and socioeconomic status. We obtained the number of decayed, missing, or filled teeth per person (dmft) from dental examinations. Logistic regression analysis was performed to estimate the odds ratio for S-ECC. The average number of decayed, missing, and filled teeth (dmft index) was 0.77. The prevalence of dental caries was 20.6%. There was at least 1 smoker in the homes of 1,370 subjects (60.2%). After excluding items of multicollinearity, the results of multivariate analysis were as follows: drinking or eating sweets after dinner, irregular snack times, parents brushing their child’s teeth less frequently, existence of smokers in the home, and no residence tax were significantly associated with S-ECC. This study suggests that there is a significant association between ETS from family members and S-ECC.

scholarly journals Human Genetics Society of Australasia Position Statement: Population-Based Carrier Screening for Cystic Fibrosis

2014 ◽  
Vol 17 (6) ◽  
pp. 578-583 ◽  
Author(s):  
Martin B. Delatycki ◽  
Jo Burke ◽  
Louise Christie ◽  
Felicity Collins ◽  
Michael Gabbett ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Human Genetics ◽  
Genetic Disorder ◽  
Position Statement ◽  
Population Based ◽  
Heterozygous Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Common Life ◽  
Cystic Fibrosis Transmembrane

Since the discovery in 1989 that mutations in cystic fibrosis transmembrane conductance regulator (CFTR) underlie cystic fibrosis (CF), the most common life shortening genetic disorder in Caucasians, it has been possible to identify heterozygous mutation carriers at risk of having affected children. The Human Genetics Society of Australasia has produced a position statement with recommendations in relation to population-based screening for CF. These include: (1) that screening should be offered to all relatives of people with or carriers of CF (cascade testing) as well as to all couples planning to have children or who are pregnant; (2) the minimum CFTR mutation panel to be tested consists of 17 mutations which are those mutations that are associated with typical CF and occur with a frequency of 0.1% or higher among individuals diagnosed with CF in Australasia; (3) that genetic counselling is offered to all couples where both members are known to have one or two CFTR mutations and that such couples are given the opportunity to meet with a physician with expertise in the management of CF as well as a family/individual affected by the condition.

scholarly journals Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel FAM20C Variant

2021 ◽  
pp. 1-5
Author(s):  
Nazan Eras ◽  
Yalcin Celik
Keyword(s):  
Genetic Disorder ◽  
Bone Dysplasia ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Compound Heterozygous ◽  
Homozygous Mutation ◽  
Limited Information ◽  
Sequencing Platform ◽  
Gene Sequence Analysis ◽  
Raine Syndrome

Raine syndrome (RS) is a rare genetic disorder characterized by osteosclerotic bone dysplasia caused by a homozygous mutation, compound heterozygous mutation, or microdeletion in the FAM20C gene. In the present study, the MiSeq next-generation sequencing platform was used to perform the FAM20C gene sequence analysis. A novel homozygous variant c.1255T>C (p.W419R) in the FAM20C gene was diagnosed, and a nonlethal RS phenotype was confirmed, thus contributing to the expansion of the nonlethal RS phenotype. Since there is limited information about rare diseases, we believe that these studies will contribute to the literature and to the understanding of how these disorders develop and progress.

scholarly journals ABCG5/G8: a structural view to pathophysiology of the hepatobiliary cholesterol secretion

2019 ◽  
Vol 47 (5) ◽  
pp. 1259-1268 ◽  
Author(s):  
Aiman A. Zein ◽  
Rupinder Kaur ◽  
Toka O.K. Hussein ◽  
Gregory A. Graf ◽  
Jyh-Yeuan Lee
Keyword(s):  
Structural Information ◽  
Genetic Disorder ◽  
Structural Features ◽  
Sterol Transport ◽  
Cholesterol Excretion ◽  
Function Relationship ◽  
Cholesterol Secretion ◽  
First Time ◽  
Mechanistic View ◽  
Inactivating Mutations

Abstract The ABCG5/G8 heterodimer is the primary neutral sterol transporter in hepatobiliary and transintestinal cholesterol excretion. Inactivating mutations on either the ABCG5 or ABCG8 subunit cause Sitosterolemia, a rare genetic disorder. In 2016, a crystal structure of human ABCG5/G8 in an apo state showed the first structural information on ATP-binding cassette (ABC) sterol transporters and revealed several structural features that were observed for the first time. Over the past decade, several missense variants of ABCG5/G8 have been associated with non-Sitosterolemia lipid phenotypes. In this review, we summarize recent pathophysiological and structural findings of ABCG5/G8, interpret the structure-function relationship in disease-causing variants and describe the available evidence that allows us to build a mechanistic view of ABCG5/G8-mediated sterol transport.

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